This application requests SERCA support for Timothy J. Stein, DVM. Dr. Stein received his veterinary degree from Iowa State University in 2001, which he followed with a one-year internship in surgery and oncology. He is completing his second year of PhD training at the University of Wisconsin-Madison in the laboratory of Eric P. Sandgren, VMD, PhD. Dr. Stein's career objective is to become a biomedical scientist who combines his veterinary and research training to study disease at the interface between basic science and clinical medicine. The overall scientific goal of Dr. Stein's proposed research is to characterize mechanisms by which mutations in beta-catenin contribute to the development of hepatocellular carcinoma, a serious disease in the human populations. Mutations in beta-catenin have been identified in 25-50% of human liver tumors, yet the functional consequences of these mutations are unclear. Dr. Stein will use an inducible transgene system to study the effects of expressing mutant beta-catenin in fetal versus adult hepatocytes. He then will employ the newly developed comparative hepatocyte growth assay, an in vivo hepatocyte transplantation system to evaluate genetically altered hepatocytes, that permits quantification of (1) the rate at which hepatocytes proliferate under growth stimulatory conditions, (2) their capacity for sustained growth in a quiescent liver environment, and (3) their risk for progression to malignant disease. Finally, he will examine lesion pathogenesis in the liver of mice expressing mutant beta-catenin together with the loss of the p53 tumor suppressor gene, a commonly identified genetic alteration in human hepatocellular carcinomas. Collectively, these studies will allow Dr. Stein to define a role for beta-catenin in multistage liver carcinogenesis. The University of Wisconsin-Madison provides an outstanding research environment. Dr. Sandgren's laboratory and colony are fully equipped to provide all resources necessary to conduct detailed gross, microscopic, and molecular evaluation of experimental mice. The laboratory is housed in the School of Veterinary Medicine. Dr. Stein will interact, formally and informally, with additional faculty and trainees in the UW-Madison Comprehensive Cancer Center and the McArdle Laboratory for Cancer Research. Dr. Stein's research training program and the excellent resources available on this campus will ensure a productive training period that will prepare Dr. Stein for independent biomedical research.